Carbapenem antibacterial compounds, compositions containing such compounds and method of treatment

ABSTRACT

Compounds of formula I:as well as pharmaceutically acceptable salts therefor and compositions useful as carbapenem antibacterial agents are disclosed.

This application claims the benefit of U.S. Provisional Application No.60/090,684, filed Jun. 25, 1998.

BACKGROUND OF THE INVENTION

The present invention relates to carbapenem antibacterial agents inwhich the carbapenem nucleus is substituted at the 2-position with a9,9-dioxo-10H -9-thia-10-aza-phenanthrene linked through a CH₂ group.

The carbapenems of the present invention are useful against grampositive microorganisms, especially methicillin resistant Staphylococcusaureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE),and methicillin resistant coagulase negative Staphylococci (MRCNS). Theantibacterial compounds of the present invention thus comprise animportant contribution to therapy for treating infections caused bythese difficult to control pathogens. There is an increasing need foragents effective against such pathogens (MRSA/MRCNS) which are at thesame time relatively free from undesirable side effects.

SUMMARY OF THE INVENTION

The compounds of the invention are represented by formula I:

including pharmaceutically acceptable salts thereof, wherein:

R¹ represents H or methyl;

CO₂M represents a carboxylic acid, a pharmaceutically acceptablecarboxylic acid salt, carboxylate anion, a pharmaceutically acceptableester group or a carboxylic acid protected by a protecting group;

P represents hydrogen, hydroxyl, F or hydroxyl protected by ahydroxyl-protecting group;

Each R independently represents R^(b),

 C₂₋₆ alkenyl, or a group L—Q—RQ with the proviso that only one R groupof the type L—Q—R^(q) can be present or one R group may be taken with L,if present, and any intervening atoms to represent a 5-6 membered ring;

L is C₁₋₄ straight or branched alkylene, uninterrupted, interrupted orterminated by 1-2 of O, S, NR^(a), C(O), CO₂ and C(O)NR^(a);

Q represents:

Y⁻ is a charge balancing group;

n is a value from 0 to 2 selected to maintain overall charge neutrality;

R^(a) is H or C₁₋₆ alkyl;

R^(q) is C₁₋₆ alkyl, straight or branched, uninterrupted, interrupted orterminated by 1-2 of O, S, NR^(a), C(O), C(O)O, C(O)NR^(a) , —CH═CH—,—Het(R^(b))₃—, —C(O)Het(R^(b))₃—,—C(O)NR^(a)Het(R^(b))₃—,

said R^(q) being unsubstituted or substituted with 1-3 R^(c) groups;

Het is a heteroaryl group;

each R^(b) is independently selected from H, halo, OR^(a), OC(O)R^(a),C(O)R^(a), CN, C(O)NR^(a)R^(d), NO₂, NR^(a)R^(d), SO₂NR^(a)R^(d) andC₁₋₄ alkyl unsubstituted or substituted with 1-3 groups selected fromR^(e);

each R^(c) is independently selected from halo, OR^(f), OC(O)R^(f),SR^(f), S(O)R^(f), SO₂R^(f), CN, C(O)R^(f), CO₂R^(f), NR^(f)R^(g),N⁺R^(a)R^(f)R^(g)Z⁻, C(O)NR^(a)R^(f), —Het(R^(b))₃,C(═N⁺R^(a)R^(f))R^(a)Z⁻, C(═N⁺R^(a)R^(f)NR^(a)R^(f)Z⁻,NR^(a)C(═N⁺R^(a)R^(f))R^(a)Z⁻, NR^(a)C(═N⁺R^(a)R^(f))NR^(a)R^(a)Z⁻,heteroarylium(R^(b))₃Z^(−, SO) ₂NR^(a)R^(f), OC(O)NR^(a)R^(f),NR^(a)C(O)R^(f), NR^(a)C(O)NR^(a)R^(f), and

 or in the alternative, when 2 or more R^(c) groups are present, 2 R^(c)groups may be taken together with any intervening atoms to form a 3-6membered carbocyclic ring, optionally interrupted with 1-3 of O, S,NR^(g), and C(O), said ring being unsubstituted or substituted with 1-3R^(e) groups;

R^(d) is H or C₁₋₄ alkyl, or R^(a) and R^(d) taken together with anyintervening atoms represent a 4-6 membered ring;

each R^(e) is independently selected from halo, OR^(a), NR^(a)R^(d) andCONR^(a)R^(d);

R^(f) is H; C₁₋₆ straight or branched chain alkyl, unsubstituted orsubstituted with 1-3 R^(e) groups; —Het(R^(b))₃; C₃₋₆ cycloalkyl,unsubstituted or substituted with 1-3 R^(e) groups, and

or R^(a) and R^(f) together with an intervening atoms form a 4-6membered ring, optionally interrupted by O, S, NR^(a) or C(O);

R^(g) is H, C₁₋₆ alkyl, unsubstituted or substituted with 1-3 R^(e)groups; C₃₋₆ cycloalkyl, unsubstituted or substituted with 1-3 R^(e)groups; C(═N⁺R^(a)R^(f))R^(a)Z⁻ or C(═N⁺R^(a)R^(f))NR^(a)R^(f)Z⁻;

or R^(f) and R^(g) together with any intervening atoms form a 4-6membered ring optionally interrupted by O, S, NR^(a) or C(O); and

Z⁻ is a charge balancing group selected from Y⁻, a monovalent anion suchas acetate, benzoate, bromide, chloride or the like, or an internalanion such as CO₂M, where M is a negative charge.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described herein in detail using the terms definedbelow unless otherwise specified.

Carboxylate anion refers to a negatively charged group —COO⁻.

The term “alkyl” refers to a monovalent alkane (hydrocarbon) derivedradical containing from 1 to 15 carbon atoms unless otherwise defined.It may be straight or branched. Preferred alkyl groups include methyl,ethyl, propyl, isopropyl, butyl and t-butyl. When substituted, alkylgroups may be substituted with up to 3 substituent groups, selected fromR^(c) or R^(e) as defined, at any available point of attachment. Whenthe alkyl group is said to be substituted with an alkyl group, this isused interchangeably with “branched alkyl group”.

Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms,without alternating or resonating double bonds between carbon atoms. Itmay contain from 1 to 4 rings which are fused. Preferred cycloalkylgroups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Whensubstituted, cycloalkyl groups may be substituted with up to 3substituents selected from R^(c) or R^(e) as defined.

A C1-4 alkylene group refers to an alkyl group which is attached throughtwo bonds to two different atoms or substituents. The two bonds on thealkylene group can be on the same carbon atom or on different carbonatoms. See, e.g., the following:

The term “alkenyl” refers to a hydrocarbon radical straight, branched orcyclic containing from 2 to 10 carbon atoms and at least one carbon tocarbon double bond. Preferred alkenyl groups include ethenyl, propenyl,butenyl and cyclohexenyl.

The term “alkynyl” refers to a hydrocarbon radical straight or branched,containing from 2 to 10 carbon atoms and at least one carbon to carbontriple bond. Preferred alkynyl groups include ethynyl, propynyl andbutynyl.

Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and thelike, as well as rings which are fused, e.g., naphthyl, phenanthrenyland the like. An aryl group thus contains at least one ring having atleast 6 atoms, with up to five such rings being present, containing upto 22 atoms therein, with alternating (resonating) double bonds betweenadjacent carbon atoms. The preferred aryl groups are phenyl, naphthyland phenanthrenyl. Aryl groups may likewise be substituted as defined.Preferred substituted aryls include phenyl and naphthyl.

The term “heteroaryl” (Het) refers to a monocyclic aromatic hydrocarbongroup having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to10 atoms, containing at least one heteroatom, O, S or N, in which acarbon or nitrogen atom is the point of attachment, and in which one ortwo additional carbon atoms is optionally replaced by a heteroatomselected from O or S, and in which from 1 to 3 additional carbon atomsare optionally replaced by nitrogen heteroatoms, said heteroaryl groupbeing optionally substituted as described herein. Examples of this typeare pyrrole, pyridine, oxazole, thiazole and oxazine. Additionalnitrogen atoms may be present together with the first nitrogen andoxygen or sulfur, giving, e.g., thiadiazole. Examples include thefollowing:

The group L—Q—R^(q) , if present, is attached to either of the twophenyl rings of the 9,9-dioxo-10OH-9-thia-10-aza-phenanthrene group,provided that no more than one L—Q—R^(q) group is present.

Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogenatom and thus a positive charge. Examples include the following:

When a charge is shown on a particular nitrogen atom in a ring whichcontains one or more additional nitrogen atoms, it is understood thatthe charge may reside on a different nitrogen atom in the ring by virtueof charge resonance that occurs.

The term “heterocycloalkyl” refers to a cycloalkyl group (nonaromatic)in which one of the carbon atoms in the ring is replaced by a heteroatomselected from O, S or N, and in which up to three additional carbonatoms may be replaced by hetero atoms.

The terms “quaternary nitrogen” and “positive charge” refer totetravalent, positively charged nitrogen atoms including, e.g., thepositively charged nitrogen in a tetraalkylammonium group (e.g.tetramethylammonium), heteroarylium, (e.g., N-methyl-pyridinium), basicnitrogens which are protonated at physiological pH, and the like.Cationic groups thus encompass positively charged nitrogen-containinggroups, as well as basic nitrogens which are protonated at physiologicpH.

The term “heteroatom” means O, S or N, selected on an independent basis.

Halogen and “halo” refer to bromine, chlorine, fluorine and iodine.

When a group is termed “substituted”, unless otherwise indicated, thismeans that the group contains from 1 to 4 substituents thereon.

When a functional group is termed “protected”, this means that the groupis in modified form to preclude undesired side reactions at theprotected site. Suitable protecting groups for the compounds of thepresent invention will be recognized from the present application takinginto account the level of skill in the art, and with reference tostandard textbooks, such as Greene, T. W. et al. Protective Groups inOrganic Synthesis Wiley, New York (1991). Examples of suitableprotecting groups are contained throughout the specification.

In some of the carbapenem compounds of the present invention, M is areadily removable carboxyl protecting group, and/or P represents ahydroxyl which is protected by a hydroxyl-protecting group. Suchconventional protecting groups consist of groups which are used toprotectively block the hydroxyl or carboxyl group during the synthesisprocedures described herein. These conventional blocking groups arereadily removable, i.e., they can be removed, if desired, by procedureswhich will not cause cleavage or other disruption of the remainingportions of the molecule. Such procedures include chemical and enzymatichydrolysis, treatment with chemical reducing or oxidizing agents undermild conditions, treatment with a transition metal catalyst and anucleophile and catalytic hydrogenation.

Examples of carboxyl protecting groups include allyl, benzhydryl,2-naphthylmethyl, benzyl, silyl such as t-butyldimethylsilyl (TBDMS),phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl,p-nitrobenzyl, 4-pyridylmethyl and t-butyl.

Examples of suitable C-6 hydroxyethyl protecting groups includetriethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl,t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.

The carbapenem compounds of the present invention are useful per se andin their pharmaceutically acceptable salt and ester forms for thetreatment of bacterial infections in animal and human subjects. The term“pharmaceutically acceptable ester, salt or hydrate,” refers to thosesalts, esters and hydrated forms of the compounds of the presentinvention which would be apparent to the pharmaceutical chemist. i.e.,those which are substantially non-toxic and which may favorably affectthe pharmacokinetic properties of said compounds, such as palatability,absorption, distribution, metabolism and excretion. Other factors, morepractical in nature, which are also important in the selection, are costof the raw materials, ease of crystallization, yield, stability,solubility, hygroscopicity and flowability of the resulting bulk drug.Conveniently, pharmaceutical compositions may be prepared from theactive ingredients in combination with pharmaceutically acceptablecarriers. Thus, the present invention is also concerned withpharmaceutical compositions and methods of treating bacterial infectionsutilizing as an active ingredient the novel carbapenem compounds.

With respect to —CO₂M, which is attached to the carbapenem nucleus atposition 3, this represents a carboxylic acid group (M represents H), acarboxylate anion (M represents a negative charge), a pharmaceuticallyacceptable carboxylic acid salt (M represents a salt forming group), apharmaceutically acceptable ester (M represents an ester forming group)or a carboxylic acid protected by a protecting group (M represents acarboxyl protecting group).

The pharmaceutically acceptable salts referred to above may take theform —COOM, where M is a negative charge, which is balanced by apositively charged Q group counterion, if the positively charged Q groupcontains more than one positive charge, a negatively charged counterionis present which in combination with the carboxylate anion, providesoverall charge neutrality. Other pharmaceutically acceptable counterionsmay be calcium, magnesium, zinc, ammonium, or alkylammonium cations suchas tetramethylammonium, tetrabutylammonium, choline,triethylhydroammonium, meglumine, triethanolhydroammonium, etc.

The pharmaceutically acceptable salts referred to above also includeacid addition salts. Thus, the Formula I compounds can be used in theform of salts derived from inorganic or organic acids. Included amongsuch salts are the following: acetate, adipate, alginate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

Acid addition salts of the compounds of formula I include compounds thatcontain a protonated, basic moiety in R. Compounds containing a basicmoiety in R are capable of protonation in aqueous media near pH 7, sothat the basic moiety can exist as an equilibrium mixture of its neutralform and acid addition (protonated) form. The more basic the group, thegreater the degree of protonation near pH 7. For example, —NR^(f)R^(g)would likely be present in its protonated form, (—N+HR^(f)R^(g)Z⁻) atthe appropriate pH, where Z⁻ is a charge balancing group. All suchcompounds are included in the present invention.

The pharmaceutically acceptable esters are such as would be readilyapparent to a medicinal chemist, and include, for example, thosedescribed in detail in U.S. Pat. No. 4,309,438. Included within suchpharmaceutically acceptable esters are those which are hydrolyzed underphysiological conditions, such as pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, and others described in detail inU.S. Pat. No. 4,479,947. These are also referred to as “biolabileesters”.

Biolabile esters are biologically hydrolizable, and may be suitable fororal administration, due to good absorption through the stomach orintenstinal mucosa, resistance to gastric acid degradation and otherfactors. Examples of biolabile esters include compounds in which Mrepresents an alkoxyalkyl, alkylcarbonyloxyalkyl,alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl,alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl,arylthioalkyl or alkylthioaryl group. These groups can be substituted inthe alkyl or aryl portions thereof with acyl or halo groups. Thefollowing M species are examples of biolabile ester forming moieties:acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl,1-isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl,phthalidyl and (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl.

Z⁻ and Y⁻ can be present or absent as necessary to maintain theappropriate charge balance. When present, these representpharmaceutically acceptable counterions. Most anions derived frominorganic or organic acids are suitable. Representative examples of suchcounterions are the following: acetate, adipate, aminosalicylate,anhydromethylenecitrate, ascorbate, aspartate, benzoate,benzenesulfonate, bromide, citrate, camphorate, camphorsulfonate,chloride, estolate, ethanesulfonate, fumarate, glucoheptanoate,gluconate, glutamate, lactobionate, malate, maleate, mandelate,methanesulfonate, pantothenate, pectinate, phosphate/diphosphate,polygalacturonate, propionate, salicylate, stearate, succinate, sulfate,tartrate and tosylate. Other suitable anionic species will be apparentto the ordinarily skilled chemist.

Likewise, when more than one negative charge is necessary to maintaincharge neutrality, the counterion indicator may represent a specie withmore than one negative charge, such as malonate, tartrate orethylenediaminetetraacetate (EDTA), or two or more monovalent anions,such as chloride, etc. When a multivalent negatively charged counterionis present with a carbapenem which bears a net single positive charge,an appropriate number of carbapenem molecules can be found inassociation therewith to maintain the overall charge balance andneutrality.

Numbering and nomenclature used in naming the sultam side chains are asfollows:

When L is a C₁₋₄ straight or branched alkylene group that is interruptedor terminated by 1-2 of O, S, NR^(a), C(O), CO₂ and C(O)NR^(a), theinterrupting/terminating moiety or moieties can be at either end of thealkylene group, as well as interrupting the alkylene group when 2-4carbon atoms are present. When 2 such groups are present, they may beseparate or together. Hence, interrupting or terminating groups such asOC(O) and OCO₂ are included.

Similarly, when R^(q) is C₁₋₆ alkyl, straight or branched, interruptedor terminated by 1-2 of O, S, NR^(a), C(O), C(O)O, C(O)NR^(a), —CH═CH—,—Het(R^(b))₃—. —C(O)Het(R^(b))₃—,

said R^(q) being unsubstituted or substituted with 1-3 R^(c) groups, theinterrupting/terminating groups may be separate or together, and may beat the end or ends of the alkyl group, and further may be between thealkyl group and a substituent R^(c).

When an R^(q) is substituted with at least 2 R^(c) groups, these may betaken in combination with any intervening atoms to represent a 3-6membered carbocyclic ring, said ring being optionally interrupted by 1-3of O, S, NR^(g) and C(O), and unsubstituted or substituted with 1-3R^(e) groups. Examples of groups which are represented by two R^(c)groups in combination include the following:

A subset of compounds of formula I which is of interest relates to thosecompounds where R¹ represents methyl. Within this subset, all othervariables are as originally defined.

Another subset of compounds of formula I which is of interest relates tothose compounds where CO₂M represents a carboxylate anion. Hence, M inthis instance represents a negative charge which is balanced by apositively charged group, such as in the positively charged Q group.Likewise, if the positively charged Q group contains more than onepositive charge, a negatively charged counterion may be present which incombination with the carboxylate anion, provides overall chargeneutrality.

Another subset of compounds of formula I that is of interest relates tothose compounds where P represents hydroxyl or hydroxyl protected by ahydroxyl protecting group. Within this subset, all other variables areas originally defined.

Another subset of compounds of formula I that is of interest relates tocompounds where L represents —CH₂— or —CH₂CH₂—. Within this subset, allother variables are as originally defined.

Another subset of compounds of formula I that is of interest relates tocompounds where Q represents

wherein Y⁻ represents a charge balancing group. Within this subset, allother variables are as originally defined.

Another subset of compounds of formula I that is of interest relates tocompounds where R^(q) is straight or branched C₁₋₆ alkyl, substitutedwith 1-3 R^(c) groups. Within this subset, all other variables are asoriginally defined.

Another subset of compounds of formula I that is of interest relates tocompounds where R is H, halo or C₁₋₄ alkyl unsubstituted or substitutedwith 1-3 groups selected from R^(e) Within this subset, all othervariables are as originally defined.

A preferred subset of compounds of formula I which is of interestrelates to those compounds wherein:

R′ represents CH₃;

CO₂M represents a carboxylate anion;

P represents hydroxyl or hydroxyl protected by a hydroxyl protectinggroup;

one R is L—Q—R^(Q) and each remaining R is independently H, halo or C₁₋₄alkyl unsubstituted or substituted with 1-3 groups selected from R^(e);

R^(a) is H or C₁₋₆ alkyl;

R^(d) is H or C₁₋₄ alkyl, or R^(a) and R^(d) taken together with anyintervening atoms represent a 4-6 membered ring;

R^(e) is halo, OR^(a), NR^(a)R^(d) or CONR^(a)R^(d);

L represents —CH₂— or —CH₂CH₂—;

Q represents

wherein

Y⁻ represents a charge balancing group and

R^(q) is straight or branched C₁₋₆ alkyl, optionally interrupted byC(O)NR^(a) or

 and substituted with 1-3 R^(c) groups, and

R^(c) is as originally defined.

Another preferred subset of compounds of formula relates to thosecompounds of formula I wherein:

R¹ represents methyl;

CO₂M represents a carboxylate anion;

P represents hydroxyl or hydroxyl protected by a hydroxyl protectinggroup;

one R group is L—Q—R^(q) and each remaining R is independently H, haloor C₁₋₄ alkyl unsubstituted or substituted with 1-3 groups selected fromR^(e);

R^(a) is H or C₁₋₆ alkyl;

R^(d) is H or C₁₋₄ alkyl, or R^(a) and R^(d) taken together with anyintervening atoms represent a 4-6 membered ring;

R^(e) is halo, OR^(a), NR^(a)R^(d) or CONR^(a)R^(d);

L represents —CH₂— or —CH₂CH₂—;

Q represents

wherein

Y⁻ represents a charge balancing group and

R^(q) is straight or branched C₁₋₆ alkyl, substituted with 1-3 R^(c)groups.

Representative examples of compounds of the invention are found in TableI.

TABLE I

Substituents(s) R n = 1 or 2 M 1 H Na 2 3′-Br Na 3

⊖ 4

⊖ 5

⊖ 6

⊖ 7

⊖ 8

⊖ 9

⊖ 10

⊖ 11

⊖ 12

⊖ 13

⊖ 14

⊖ 15

⊖ 16

⊖ 17

⊖ 18

⊖

The compounds of the present invention are prepared by reacting asuitably protected, activated 2-hyroxymethyl-carbapen-2-em-3-carboxylatewith a 9,9, dioxo-10H-9-thia-10-aza-phenanthrene, modifying introducedside chain as desired, and then removing any groups which are present toafford the desired final product. The process is illustrated using thegeneral conditions shown in the accompanying flow charts.

With reference to Flow Charts A and B above, P, R¹, R, M, L, Q and R^(q)are as defined with respect to the compounds of formula I.

P* represents H, F or a protected hydroxyl group.

R^(o) represents a carboxyl protecting group.

R* represents a group selected from R or a group that is modified asnecessary in the course of the synthesis of a compound of formula I toafford a member of R, thus R* an be viewed as R or a precursor to R.

P″ represents a hydroxyl protecting group.

Q′—R^(q′) represents a neutral or monocationic group that reacts withthe intermediate B2 (upon activation of B2) in a manner which results inthe incorporation in the final product of the member of the groupdefined as Q—R^(q) above, thus Q′—R^(q′) may be viewed as a precursorfor Q—R^(q).

R^(q′) represents a group selected from R^(q) or a group that ismodified or deprotected as necessary in the course of the synthesis of acompound of formula I so as to afford a member of R^(q), thus R^(q′) canbe viewed as R^(q) or as a precursor to R^(q).

The 9,9-dioxo-10H-9-thia-10-aza-phenanthrene side chain group (SCG) usedin the synthesis of the compounds of the present invention have, in somecases, been described in the chemical literature. In other cases,precursor compounds which may be readily converted to the requisite SCGhave been described in the literature. In cases where the requisite SCGis not known in the literature it is necessary to synthesize the SCG bya newly developed synthesis. One skilled in the art can adapt apreviously published synthesis of an analogous SCG to prepare therequisite compound in a straightforward manner without undueexperimentation.

The 9,9-dioxo-10H-9-thia-10-aza-phenanthrene side chain group (SCG) isinitially reacted with a suitably protected carbapen-2-em-3-carboxylatehaving an activated hydroxymethyl group at the 2-position. Thecarbapenem nucleus having a —CH₂OH substituent at position 2 can beobtained in accordance with Schmitt, S. M. et al., J. Antibiotics 41(6):780-787 (1988), the teachings of which are incorporated herein byreference.

The carboxylic acid group at C-3 of the carbapenem is generallyprotected as a carboxyl protecting group such as p-nitrobenzyl (PNB),allyl, p-methoxybenzyl, trichloroethyl, 2-trimethylsilylethyl, and thelike. Furthermore, the hydroxyl group of the 6-(hydroxyethyl) side-chainis optionally protected with a hydroxyl protecting group such astrimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl(TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl, allyloxycarbonyl,2-trimethylsilylethoxy carbonyl, 2-trichloroethoxycarbonyl and the like.

The addition of 9,9-dioxo-10H-9-thia-10-aza-phenanthrene side chaingroup (SCG) to the carbapenem is accomplished by treating a solution ofthe hydroxymethyl-carbapenem and the9,9-dioxo-10H-9-thia-10-aza-phenanthrene side chain group in a suitablesolvent such as tetrahydrofuran (THF), diethyl ether, acetonitrile,dimethylformamide (DMF), benzene, dichloromethane, chloroform, and thelike with a (premixed) suitable activating reagent such as diethylazodicarboxylate (DEAD)/triphenylphosphine, diisopropyl azodicarboxylate(DIAD)/tributylphosphine, and the like, at a temperature between about−20° C. and 35° C. for about 5 to 90 minutes.

Alternatively, the 9,9-dioxo-10H-9-thia-10-aza-phenanthrene andcarbapenem can be mixed together with either the azodicarboxylate or thephosphine reagent in a suitable solvent and the other component of theactivating reagent (the phosphine or the azodicarboxylate, respectively)can be added to that mixture. Once the9,9-dioxo-10H-9-thia-10-aza-phenanthrene, the carbapenem and activatingreagent(s) have been mixed, the reaction is allowed to proceed at atemperature between about −20° C. and 35° C. for about 5 to 90 minutes.

The resulting mixture is then subjected to a standard work-up procedurefamiliar to those skilled in the art to afford a crude2-(9,9-dioxo-10H-9-thia-10-aza-phenanthrene-10-yl) methyl substitutedcarbapenem which is purified, if necessary, by recrystallization or bychromatography on silica gel, eluting with a suitable solvent or mixtureof two or more solvents, such as hexane, ethyl acetate, ether, benzene,dichloromethane, chloroform, acetone, methanol and the like.

In some cases, it is necessary to modify substituent R* in intermediateA2 to produce the desired substituent R in final product I. Modificationof the R* substituent is generally best accomplished before the removalof the protecting groups P* and R^(o). This process is illustrated inFlow Chart B in which intermediate B1 is an example of intermediate A2wherein one of the R* groups is a precursor to the substituent L—Q—R^(q). The skilled artisan should note that the substituent L—Q—R^(q) can belocated in either of the phenyl rings of the final product Ib eventhough the scheme illustrates the process for one ring only.

In intermediate B1 of Flow Chart B, the substituent R* is represented asL—OP″, wherein L is as previously defined and P″ is a hydroxylprotecting group. Suitable protecting groups P″ are trimethylsilyl andtriethylsilyl. The trialkylsilyl group is easily removed by treatmentwith a strong acid such as trifluoromethane sulfonic acid, sulfuricacid, hydrochloric acid, or the the like in a solvent consisting ofwater plus a miscible organic solvent such as tetrahydrofuran,acetonitrile , or isopropanol. A positively charged substituent may beintroduced into the side chain by first activating the hydroxyl group ofL—OH by converting it to a suitable leaving group such as a triflate,mesylate, tosylate, iodide, chloride, bromide, and the like, and thendisplacing the resulting leaving group with a compound Q′—R^(q′) such asN-methyl-imidazole, N-(2-hydroxyethyl)-imidazole,1-methyl-4-aza-1-azoniabicyclo[2.2.2]octane,1-(carbamoylmethyl)-4-aza-1-azoniabicyclo-[2.2.2.]-octane,1-(3-hydroxyprop-1-yl)-4-aza-1-azoniabicyclo-[2.2.2.]-octane, and thelike which contains a nitrogen atom that can act as a nucleophile.

In some cases, activation of the hydroxyl group and displacement byQ′—R^(q′) to produce B3 may be accomplished in a single step by takingadvantage of the basic character of compound Q′—R^(q′) and using it as abase in the activation reaction.

The conversion of the hydroxyl group to a suitable leaving group isaccomplished by treating the hydroxyl substituted compound in a suitablesolvent such as dichloromethane, tetrahydrofuran, ether, benzene, andthe like with an activating reagent, such as trifluoromethanesulfonicanhydride, methanesulfonic anhydride, toluenesulfonic anhydride,methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonylchloride, and the like in the presence of a suitable base such astriethylamine, tributylamine, diisopropylethylamine, and the like at atemperature between about −100° C. and 0° C. for about 5 to 120 minutes.The intermediate thus obtained contains a leaving group, which may beconverted to an alternative leaving group, iodide, by treating asolution of the intermediate in a suitable solvent such as acetone,methyl ethyl ketone, and the like at about −10° C. to 50° C. with anexcess of sodium iodide or potassium iodide for about 0.25 to 24 hours.

In many cases, the iodide is obtained in sufficiently pure form that itmay be used without further purification. For ease of handling, theiodide, if not crystalline, may be lyophilized from benzene to afford anamorphous, easily handled, solid.

The activated hydroxyl group or iodide is displaced by reacting theactivated intermediate with reagent Q′—R^(q′). In some cases, activationand displacement of the hydroxyl group may be accomplished in a singlestep. The activating reagent is added to a solution of the hydroxylsubstituted compound in the presence of a suitable base in a suitablesolvent such as dichloromethane, tetrahydrofuran, ether, DMF, benzene,acetonitrile, DMSO, and the like as described in the precedingparagraphs. The resulting activated intermediate is treated with 1-3molar equivalents of compound Q′—R^(q′) at a temperature between about−78° C. and 50° C. for about 15 to 120 minutes. In some cases, it isdesirable to form the activated intermediate in one solvent, isolate theactivated intermediate, and conduct the displacement reaction in adifferent solvent. In other cases, the displacement may be conductedwithout isolation of the intermediate and, in cases where Q′—R^(q′) isalso used as a base, may even be concurrent with the formation of theactivated intermediate.

In cases where the displacement reaction is best accomplished by usingthe iodide, a solution of the iodide is combined with an approximatelyequivalent amount (0.9-1.05 molar equivalents) of compound Q′—R^(q′). Asilver salt of a non-nucleophilic acid, such as silvertrifluoromethanesulfonate, silver tetrafluoroborate and the like is thenadded. Although the reaction will proceed in the absence of the silversalt, the reaction proceeds more rapidly in the presence of the silversalt. In addition, the silver salt assists in the removal of thedisplaced iodide from the reaction mixture which can improve theefficiency of subsequent steps. The resulting mixture is then subjectedto a standard work-up procedure familiar to those skilled in the art toafford a crude product which is purified, if necessary, byrecrystallization or chromatography.

An alternative method for introducing a positive charge into the sidechain may be applied to side chains (i.e. R* groups) that contain anitrogen atom which may be quaternized by reaction with a suitablealkylating reagent AR, such as methyl iodide, methyl bromide, benzyltrichloroacetimidate, methyl trifluoromethanesulfonate, triethyloxoniumtetrafluoroborate, and the like. Quaternization of the nitrogen atom inthe side chain is effected by treating a solution of the compound with aslight excess (1.05 to 1.2 molar equivalents) of the alkylating reagent.

Modification of the substituent R^(q′), if necessary, and removal of theremaining protecting group(s) affords the final product (Ib). Thesetransformations can be accomplished by a number of well known techniquesdepending on the protecting groups employed or the modificationsrequired to transform R^(q′) to R^(q) or the protecting groups employed.

For example, when R^(q) of the final product contains a primary aminogroup (—NH₂ or —N⁺H₃ in its protonated form), the amino group wouldnormally be present in R^(q′) as a protected form or as a precursorgroup. Suitably protected forms of the amino group areallyloxycarbonylamino or p-nitrobenzyloxycarbonylamino whereas assuitable amine precursor is an azido group. The amino group is liberatedby established methodology either concurrent with or after thedeblocking of P* and R^(o). For example, the azido andp-nitrobenzyloxycarbonylamino groups can be converted to the amino groupby catalytic hydrogenation and the allyloxycarbonylamino group providesthe amino substituent on treatment with a palladium catalyst in thepresence of an allyl scavenger.

The synthesis of the target compound is completed by removing anyprotecting groups which are present in the penultimate intermediateusing standard techniques which are well known to those skilled in theart. The deprotected final product is then purified, as necessary, usingstandard techniques such as ion exchange chromatography, HPLC on reversephase silica gel, MPLC on reverse phase polystyrene gel, and the like orby recrystallization.

The final product may be characterized structurally by standardtechniques such as NMR, IR, MS, and UV. For ease of handling, the finalproduct, if not crystalline, may be lyophilized from water to afford anamorphous, easily handled solid.

The compounds of the present invention are valuable antibacterial agentsactive against various Gram-positive and to a lesser extentGram-negative bacteria, and accordingly find utility in human andveterinary medicine.

Many of compounds of the present invention are biologically activeagainst MRSA/MRCNS. In vitro antibacterial activity is predictive of invivo activity when the compounds are administered to a mammal infectedwith a susceptible bacterial organism.

Using standard susceptibility tests, the compounds of the invention aredetermined to be active against MRSA.

The compounds of the invention can be formulated in pharmaceuticalcompositions by combining the compound with a pharmaceuticallyacceptable carrier. Examples of such carriers are set forth below.

The compounds may be employed in powder or crystalline form, in liquidsolution, or in suspension. They may be administered by a variety ofmeans; those of principal interest include: topically, orally andparenterally by injection (intravenously or intramuscularly).

Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampules, or in multidose containers. Theinjectable compositions may take such forms as suspensions, solutions,or emulsions in oily or aqueous vehicles, and may contain variousformulating agents. Alternatively, the active ingredient may be inpowder (lyophillized or non-lyophillized) form for reconstitution at thetime of delivery with a suitable vehicle, such as sterile water. Ininjectable compositions, the carrier is typically comprised of sterilewater, saline or another injectable liquid, e.g., peanut oil forintramuscular injections. Also, various buffering agents, preservativesand the like can be included.

Topical applications may be formulated in carriers such as hydrophobicor hydrophilic bases to form ointments, creams, lotions, in aqueous,oleaginous or alcoholic liquids to form paints or in dry diluents toform powders.

Oral compositions may take such forms as tablets, capsules, oralsuspensions and oral solutions. The oral compositions may utilizecarriers such as conventional formulating agents, and may includesustained release properties as well as rapid delivery forms.

The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated, the route and frequencyof administration, the sensitivity of the pathogen to the particularcompound selected, the virulence of the infection and other factors.Such matters, however, are left to the routine discretion of thephysician according to principles of treatment well known in theantibacterial arts. Another factor influencing the precise dosageregimen, apart from the nature of the infection and peculiar identity ofthe individual being treated, is the molecular weight of the compound.

The compositions for human delivery per unit dosage, whether liquid orsolid, may contain from about 0.01% to as high as about 99% of activematerial, the preferred range being from about 10-60%. The compositionwill generally contain from about 15 mg to about 2.5 g of the activeingredient; however, in general, it is preferable to employ dosageamounts in the range of from about 250 mg to 1000 mg. In parenteraladministration, the unit dosage will typically include the pure compoundin sterile water solution or in the form of a soluble powder intendedfor solution, which can be adjusted to neutral pH and isotonic.

The invention described herein also includes a method of treating abacterial infection in a mammal in need of such treatment comprisingadministering to said mammal a compound of formula I in an amounteffective to treat said infection.

The preferred methods of administration of the Formula I antibacterialcompounds include oral and parenteral, e.g., i.v. infusion, i.v. bolusand i.m. injection.

For adults, about 5-50 mg of Formula I antibacterial compound per kg ofbody weight given one to four times daily is preferred. The preferreddosage is 250 mg to 1000 mg of the antibacterial given one to four timesper day. More specifically, for mild infections a dose of about 250 mgtwo or three times daily is recommended. For moderate infections againsthighly susceptible gram positive organisms a dose of about 500 mg threeor four times daily is recommended. For severe, life-threateninginfections against organisms at the upper limits of sensitivity to theantibiotic, a dose of about 1000-2000 mg three to four times daily maybe recommended.

For children, a dose of about 5-25 mg/kg of body weight given 2, 3, or 4times per day is preferred; a dose of 10 mg/kg is typically recommended.

The compounds of Formula I are of the broad class known as carbapenems.Many carbapenems are susceptible to attack by a renal enzyme known asdehydropeptidase (DHP). This attack or degradation may reduce theefficacy of the carbapenem antibacterial agent. Many of the compounds ofthe present invention, on the other hand, are less subject to suchattack, and therefore may not require the use of a DHP inhibitor.However, such use is optional and contemplated to be part of the presentinvention. Inhibitors of DHP and their use with carbapenems aredisclosed in, e.g.,[European Patent Application Nos. 79102616.4, filedJul. 24, 1979 (Patent No. 0 007 614); and 82107174.3, filed Aug. 9, 1982(Publication No. 0 072 014)].

The compounds of the present invention may, where DHP inhibition isdesired or necessary, be combined or used with the appropriate DHPinhibitor as described in the aforesaid patents and publishedapplication. The cited European Patent Applications define the procedurefor determining DHP susceptibility of the present carbapenems anddisclose suitable inhibitors, combination compositions and methods oftreatment. A preferred weight ratio of Formula I compound: DHP inhibitorin the combination compositions is about 1:1.

A preferred DHP inhibitor is7-(L-2-amino-2-carboxy-ethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid or a useful salt thereof.

The invention is further described in connection with the followingnon-limiting examples.

EXAMPLE 1 Sodium(1S,5R,6S)-2-(9,9-Dioxo-10H-9-Thia-10-Aza-Phenanthren-10-Ylmethyl)-6-[1(R)-Hydroxy-Ethyl]-1-Methyl-Carbapen-2-Em-3-Carboxylate

Step 1: Allyl(1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-(9,9-dioxo-10H-9-thia-10-aza-phenanthren-10-ylmethyl)-1-methyl-carbapen-2-em-3-carboxylate

A solution ofallyl(1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methlyl-carbapen-2-em-3-carboxylate(50 mg, 0.137 mmol), 9,9-dioxo-10H-9-thia-10-aza-phenanthrene (32 mg,0.137 mmol), and triphenylphosphine (54 mg, 0.206 mmol) in anhydroustetrahydrofuran (0.8 mL) was treated with diethyl azodicarboxylate(0.033 mL, 0.206 mmol). The mixture was stirred at room temperature or30 minutes, then streaked onto two 1 mm×20 cm×20 cm silica gel GFplates. The plates were developed with 5% ethyl acetate indichloromethane. The product band was removed and eluted with ethylacetate to afford allyl1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-(9,9-dioxo-10H-9-thia-10-aza-phenanthren-10-ylmethyl)-1-methyl-carbapen-2-em-3-carboxylate(22 mg) as an oil.

The 9,9-dioxo-10H-9-thia-10-aza-phenanthrene starting material used inStep 1, Example 1 can be prepared according to the procedures of Ullmanand Gross, Chem. Ber., 43, 2964, (1910) and Dewar, et al., J. Chem. Soc.Perkin Trans., 1, 2862, (1972).

Step 2: Sodium(1S,5R,6S)-2-(9,9-dioxo-10H-9-thia-10-aza-phenanthren-10-ylmethyl)-6-[1(R)-hydroxy-ethyl]-1-methyl-carbapen-2-em-3-carboxylate

The product from step 1 (22 mg, 0.038 mmol) in dichloromethane (0.5 mL)was treated with triphenylphosphine (1.6 mg, 0.0061 mmol), 0.5M sodium2-ethyl-hexanoate in ethyl acetate (0.021 mL, 0.011 mmol),2-ethyl-hexanoic acid (0.007 mL, 0.044 mmol) andtetrakis(triphenylphosphine)palladium(0) (4.4 mg, 0.0038 mmol). Themixture was stirred at room temperature for 15 minutes, then dilutedwith ethyl ether (5 mL) and centrifuged. The solid pellet was washedwith ether (1.5 mL), taken up in 20% acetonitrile in water (3 mL), andapplied to a column of Bio-Rad Macro-Prep CM weak cation exchange resin(2 mL). The column was eluted with 20% acetonitrile in water. Theproduct containing fractions were concentrated under vacuum andlyophilized to afford the title compound (13.4 mg) as an amorphoussolid.

¹H NMR (4:1 D₂O—CD₃CN, 500 Mhz) δ 1.06 (d, 1-CH₃), 1.24 (d, CH₃CHOH),2.34 (m, H-1), 3.33 (m, H-6), 3.66 (dd, H-5), 4.18 (m, CH₃CHOH), 4.96and 5.67 (two d's, 2-CH₂), 7.59-8.35 (aryl-H's)

EXAMPLE 2 (1,5R6S)-2-{6-[2-)4-Carbamoylmethyl-1,4-Diazonia-bicylo[2.2.2]Oct-1-Yl)-Ethyl]-9.9-Dioxo-10H-9-Thia-10-Aza-phenanthren-10-Ylmethyl}-6-[1(R)-Hydroxy-Ethyl]-1-Methyl-Carbapen-2-Em-3-CarboxylateChloride

Step 1: Allyl(1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-[9,9-dioxo-6-(2-triethylsilanyloxy-ethyl)-10H-9-thia-10-aza-phenanthren-10-ylmethyl)-1-methyl-carbapen-2-em-3-carboxylate

A solution of allyl(1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate(365 mg, 1.0 mmol), triphenylphosphine (315 mg, 1.2 mmol), and9,9-dioxo-6-(2-triethylsilanyloxy-ethyl)-10H-9-thia-10-aza-phenanthrene(429 mg, 1.1 mmol) in anhydrous tetrahydrofuran (7.3 mL) is cooled in anice-bath and stirred under a nitrogen atmosphere while diisopropylazodicarboxylate (0.24 mL, 1.2 mmol) is added dropwise over a fewminutes. The resulting solution is stirred in the cold for 30 minutes,then diluted with chloroform, washed with 5% aqueous sodium bicarbonateand brine, dried over sodium sulfate, filtered and evaporated undervacuum. The residue is purified by silica gel flash chromatography ,eluting with hexane-ethyl acetate, to afford allyl(1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-[9,9-dioxo-6-(2-triethylsilanyloxy-ethyl)-10H-9-thia-10-aza-phenanthren-10-ylmethyl)-1-methyl-carbapen-2-em-3-carboxylate.

Step 2: Allyl(1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2{9,9-dioxo-6-[2-(trifluoromethanesulfonyloxy)-ethyl]-10H-9-thia-10-aza-phenanthren-10-ylmethyl}-1-methyl-carbapen-2-em-3-carboxylate

The compound from step 1 (368 mg, 0.5 mmol) in tetrahydrofuran (4.0 mL)is diluted with water (1.0 mL and treated with 1M aqueoustrifluoromethanesulfonic acid (0.05 mL, 0.05 mmol). After stirring atroom temperature for 15 minutes, the reaction mixture is partitionedbetween ethyl acetate (25 mL) and 5% aqueous sodium bicarbonate (5 mL).The organic phase is washed with 50% saturated brine, dried overmagnesium sulfate, filtered, evaporated under vacuum, and stripped withanhydrous toluene to leave a residue of the desilylated alcohol.

A solution of the crude alcohol (0.5 mmol) in anhydrous dichloromethane(10 ml) is cooled in an ice-methanol bath (−20° C.) and stirred under anitrogen atmosphere. The solution is treated with 2,6-lutidine (0.175mL, 1,5 mmol) followed by trifluoromethanesulfonic anhydride (0.126 mL,0.75 mmol). After stirring at −20° to −15° C. (bath temperature) for 40minutes, the solution is diluted with dichloromethane (30 mL), washedwith water (20 mL), 0.1N hydrochloric acid (20 mL), and water (20 mL),dried over magnesium sulfate, filtered, and evaporated under vacuum oafford allyl(1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-{9,9-dioxo-6-[2-(trifluoromethanesulfonyloxy)-ethyl]-10H-9-thia-10-aza-phenanthren-10-ylmethyl}-1-methyl-carbapen-2-em-3-carboxylate.

Step 3: Allyl(1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-{6-[2-)4-carbamoylmethyl-1,4-diazonia-bicyclo[2.2.2]oct-1-yl)-ethyl]-9,9-dioxo-10H-9-thia-10-aza-phenanthren-10-ylmethy]}-1-methyl-carbapen-2-em-3-carboxylatebis(trifluoromethanesulfonate)

A sample (94 mg, 0.125 mmol) of the triflate derivative prepared asdescribed in step 2 is dissolved in anhydrous acetonitrile (1.0 mL) andthe solution is treated with1-carbamoylmethyl-1-azonia-4-aza-bicyclo[2.2.2]octanetrifluoromethanesulfonate (44 mg, 0.14 mmol). The reaction mixture isstirred at room temperature for 90 minutes, then evaporated under vacuumto a residue which is aged an additional 90 minutes at room temperature.The residue is triturated with anhydrous diethyl ether to afford allyl(1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-{6-[2-)4-carbamoylmethyl-1,4-diazonia-bicyclo[2.2.2]oct-1-yl)-ethyl]-9,9-dioxo-10H-9-thia-10-aza-phenanthren-10-ylmethyl]}-1-methyl-carbapen-2-em-3-carboxylatebis(trifluoromethanesulfonate).

Step 4:(1S,5R,6S)-2-{6-[2-)4-carbamoylmethyl-1,4-diazonia-bicyclo[2.2.21oct-1-yl)-ethyl]-9,9-dioxo-10H-9-thia-10-aza-phenanthren-10-ylmethyl}]-6-[1(R)-hydroxy-ethyl]-1-methyl-carbapen-2-em-3-carboxylatechloride

The crude bisprotected intermediate of step 3 (approximately 0.125mmol), triphenylphosphine (4.9 mg, 0.0187 mmol), dimedone (53 mg, 0.378mmol), and tetrakis(triphenylphosphine)-palladium(0) (7.2 mg, 0.0062mmol) are dissolved in anhydrous dimethylformamide (1.3 mL). Thesolution is purged with nitrogen, then treated withN,N-diisopropylethylamine (0.065 mL, 0.373 mmol). After stirring at roomtemperature for 15 minutes, the reaction mixture is added to diethylether to precipitate the crude product. The precipitate is trituratedwith ether (2×5 mL) and dried under vacuum. The precipitate in 1:1acetonitrile-water (1 mL) is added to a column of Macro-Prep CM(Bio-Rad) weak cation exchange resin (3 mL). The column is successivelyeluted with 1:1 acetonitrile-water (4 mL), water (3×5 mL), and 5%aqueous sodium chloride (5×3 mL). The product containing sodium chloridefractions are pooled, cooled in ice, and loaded onto a column ofAmberchrom CG-161 (TosoHaas) resin (3 mL). The Amberchrom column iseluted with ice-cold water (3×5 mL) followed by 20% isopropanol in water(10×3 mL). The product containing aqueous isopropanol fractions arecombined, concentrated under vacuum to remove the isopropanol, andlyophilized to afford the title compound as an amorphous solid.

EXAMPLES 3-12

By appropriately modifying the procedure of Examples 1 and 2, thefollowing compounds are prepared:

TABLE 2

Ex. Q—R^(q) Ex. Q—R^(q) 3

6

4

7

5

Ex. Q—R^(q) Ex. Q—R^(q) 8

9

Ex. Q—R^(q) 10

11

12

13

14

15

Ex. Q—R^(q) Ex. Q—R^(q) 16

17

What is claimed is:
 1. A compound represented by formula I:

including pharmaceutically acceptable salts thereof, wherein: R¹represents H or methyl; CO₂M represents a carboxylic acid, orcarboxylate anion, provided that when CO₂M represents a carboxylateanion it is balanced by Q; P represents hydrogen, hydroxyl or F; each Rindependently represents R^(b),

 C₂₋₆ alkenyl, or a group L—Q—R^(q) with the proviso that only one Rgroup of the type L—Q—R^(q) can be present; L is C₁₋₄ straight orbranched alkylene, uninterrupted, or interrupted by 1-2 of O, S, NR^(a),C(O), CO₂ and C(O)NR^(a); Q represents:

Y⁻ is a charge balancing group; n is a value from 1 to 2 selected tomaintain overall charge neutrality; R^(a) is H or C1-6 alkyl; R^(q) isC₁₋₆ alkyl, straight or branched, uninterrupted or interrupted by 1-2 ofO, S, NR^(a), C(O), C(O)O, C(O)NR^(a), —CH═CH—, —Het(R^(b))₃—,—C(O)Het(R^(b))₃—,—C(O)NR^(a)Het(R^(b))₃—,

said R^(q) being unsubstituted or substituted with 1-3 R^(c) groups; Hetis a heteroaryl group; each R^(b) is independently selected from H,halo, OR^(a), OC(O)R^(a), C(O)R^(a), CN, C(O)NR^(a)R^(d), NO₂,NR^(a)R^(d), SO₂NR^(a)R^(d) and C₁₋₄ alkyl unsubstituted or substitutedwith 1-3 groups selected from R^(e); each R^(c) is independentlyselected from halo, OR^(f), OC(O)R^(f), SR^(f), S(O)R^(f), SO₂R^(f), CN,C(O)R^(f), CO₂R^(f), NR^(f)R^(g), N⁺R^(a)R^(f)R^(g)Z⁻, C(O)NR^(a)R^(f),−Het(R^(b))₃, C(═N⁺R^(a)R^(f))R^(a)Z⁻, C(═N⁺R^(a)R^(f))NR^(a)R^(f)Z⁻,NR^(a)C(═N⁺R^(a)R^(f))R^(a)Z⁻, NR^(a)C(═N⁺R^(a)R^(f))NR^(a)R^(f)Z⁻,heteroarylium(R^(b))₃Z⁻, SO₂NR^(a)R^(f), OC(O)NR^(a)R^(f),NR^(a)C(O)R^(f), NR^(a)C(O)NR^(a)R^(f), and

or in the alternative, when 2 or more R^(c) groups are present, 2 R^(c)groups may be taken together with any intervening atoms to form a 3-6membered carbocyclic ring, optionally interrupted with 1-3 of O, S,NR^(g), and C(O), said ring being unsubstituted or substituted with 1-3R^(e) groups; R^(d) is H or C₁₋₄ alkyl, or each R^(e) is independentlyselected from halo, OR^(a), NR^(a)R^(d) and CONR^(a)R^(d); R^(f) is H;C₁₋₆ straight or branched chain alkyl, unsubstituted or substituted with1-3 R^(e) groups; —Het(R^(b))₃; C₃₋₆ cycloallkyl, unsubstituted orsubstituted with 1-3 R^(e) groups, and

R^(g) is H, C₁₋₆ alkyl, unsubstituted or substituted with 1-3 R^(e)groups; C₃₋₆ cycloalkyl, unsubstituted or substituted with 1-3 R^(e)groups; C(═N⁺R^(a)R^(f))R^(a)Z⁻ or C(═N⁺R^(a)R^(f))NR^(a)R^(f)Z⁻, and Zis a charge balancing group selected from Y⁻.
 2. A compound inaccordance with claim 1 wherein R¹ represents methyl.
 3. A compound inaccordance with claim 1 wherein CO₂M represents a carboxylate anion. 4.A compound represented by the formula:


5. A compound represented by the formula:


6. A compound in accordance with claim 1 wherein P represents hydroxyl.7. A compound in accordance with claim 1 wherein L represents —CH₂— or—CH₂CH₂—.
 8. A compound in accordance with claim 1 wherein Q represents

wherein Y⁻ represents a charge balancing group, and n is 1 to
 2. 9. Acompound in accordance with claim 1 wherein R^(q) is straight orbranched C₁₋₆ alkyl, substituted with 1-3 R^(c) groups.
 10. A compoundin accordance with claim 1 wherein R is H, halo or C₁₋₄ alkylunsubstituted or substituted with 1-3 groups selected from R^(e).
 11. Acompound in accordance with claim 1 wherein: R¹ represents CH₃; CO₂Mrepresents a carboxylate anion; P represents hydroxyl; one R isL—Q—R^(q) and each remaining R is independently H, halo or C₁₋₄ alkylunsubstituted or substituted with 1-3 groups selected from R^(e); R^(a)is H or C₁₋₆ alkyl; R^(d) is H or C₁₋₄ alkyl; R^(e) is halo, OR^(a),NR^(a)R^(d) or CONR^(a)R^(d); L represents —CH₂— or —CH₂CH₂—; Qrepresents

wherein Y⁻ represents a charge balancing group, and n is 1 to 2; andR^(q) is straight or branched C₁₋₆ alkyl, optionally interrupted byC(O)NR^(a) or

 and  substituted with 1-3 R^(c) groups, and R^(c) is as originallydefined.
 12. A compound in accordance with claim 1 wherein: R¹represents methyl; CO₂M represents a carboxylate anion; P representshydroxyl; one R group is L—Q—R^(q) and each remaining R is independentlyH, halo or C₁₋₄ alkyl unsubstituted or substituted with 1-3 groupsselected from R^(e); R^(a) is H or C₁₋₆ alkyl; R^(d) is H or C₁₋₄ alkyl;R^(e) is halo, OR^(a), NR^(a)R^(d) or CONR^(a)R^(d); L represents —CH₂—or —CH₂CH₂—; Q represents

wherein Y⁻ represents a charge balancing group, and n is 1 to 2; andR^(q) is straight or branched C₁₋₆ alkyl, substituted with 1-3 R^(c)groups.
 13. A carbapenem compound represented by the formulas in Table 1wherein three R(s) are H in compounds 3 through 18: TABLE I

Substituents(s) R n = 1 or 2 M 1 H Na 2 3′-Br Na 3

⊖ 4

⊖ 5

⊖ 6

⊖ 7

⊖ 8

⊖ 9

⊖ 10

⊖ 11

⊖ 12

⊖ 13

⊖ 14

⊖ 15

⊖ 16

⊖ 17

⊖ 18

⊖.


14. A compound represented by the formulas in Table 2: TABLE 2

Ex. Q—R^(q) Ex. Q—R^(q) 3

6

4

7

5

Ex. Q—R^(q) Ex. Q—R^(q) 8

9

Ex. Q—R^(q) 10

11

13

14

Ex. Q—R^(q) Ex. Q—R^(q) 15

16

.


15. A pharmaceutical composition comprised of a compound in accordancewith claim 1 in combination with a pharmaceutically acceptable carrier.16. A method of treating a bacterial infection comprising administeringto a mammalian patient in need of such treatment a compound as definedin claim 1 in an amount which is effective for treating a bacterialinfection.